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Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2022 , DOI: 10.1172/jci140508
Bo-Yi Sung , Yi-Hsin Lin , Qiongman Kong , Pali D. Shah , Joan Glick Bieler , Scott Palmer , Kent J. Weinhold , Hong-Ru Chang , Hailiang Huang , Robin K. Avery , Jonathan Schneck , Yen-Ling Chiu

T cell polyfunctionality is a hallmark of protective immunity against pathogens and cancer, yet the molecular mechanism governing it remains mostly elusive. We found that canonical Wnt agonists inhibited human memory CD8+ T cell differentiation while simultaneously promoting the generation of highly polyfunctional cells. Downstream effects of Wnt activation persisted after removal of the drug, and T cells remained polyfunctional following subsequent cell division, indicating the effect is epigenetically regulated. Wnt activation induced a gene expression pattern that is enriched with stem cell–specific gene signatures and upregulation of protein arginine methyltransferase 1 (PRMT1), a known epigenetic regulator. PRMT1+CD8+ T cells are associated with enhanced polyfunctionality, especially the ability to produce IL-2. In contrast, inhibition of PRMT1 ameliorated the effects of Wnt on polyfunctionality. Chromatin immunoprecipitation revealed that H4R3me2a, a permissive transcription marker mediated by PRMT1, increased at the IL-2 promoter loci following Wnt activation. In vivo, Wnt-treated T cells exhibited superior polyfunctionality and persistence. When applied to cytomegalovirus (CMV) donor–seropositive, recipient-seronegative patients (D+/R–) lung transplant patient samples, Wnt activation enhanced CMV-specific T cell polyfunctionality, which is important in controlling CMV diseases. These findings reveal a molecular mechanism governing T cell polyfunctionality and identify PRMT1 as a potential target for T cell immunotherapy.

中文翻译:

Wnt 激活通过表观遗传调节器 PRMT1 促进记忆 T 细胞多功能性

T 细胞多功能性是针对病原体和癌症的保护性免疫的标志,但控制它的分子机制仍然大多难以捉摸。我们发现经典的 Wnt 激动剂抑制人类记忆 CD8 + T 细胞分化,同时促进高度多功能细胞的生成。去除药物后,Wnt 激活的下游效应持续存在,并且 T 细胞在随后的细胞分裂后仍保持多功能,表明该效应受到表观遗传调控。Wnt 激活诱导了一种基因表达模式,该模式富含干细胞特异性基因特征和蛋白质精氨酸甲基转移酶 1 (PRMT1)(一种已知的表观遗传调节因子)的上调。PRMT1 + CD8 + T 细胞与增强的多功能性相关,尤其是产生 IL-2 的能力。相反,抑制 PRMT1 可以改善 Wnt 对多功能性的影响。染色质免疫沉淀显示,H4R3me2a(一种由 PRMT1 介导的许可转录标记)在 Wnt 激活后在 IL-2 启动子位点处增加。在体内,Wnt 处理的 T 细胞表现出优异的多功能性和持久性。当应用于巨细胞病毒 (CMV) 供体血清阳性、受体血清阴性患者 (D+/R–) 肺移植患者样本时,Wnt 激活增强了 CMV 特异性 T 细胞的多功能性,这对于控制 CMV 疾病非常重要。这些发现揭示了控制 T 细胞多功能性的分子机制,并将 PRMT1 确定为 T 细胞免疫治疗的潜在靶点。
更新日期:2022-01-19
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